Prophylaxis of graft-versus-host disease by lentiviral-mediated expression of herpes simplex virus-thymidine kinase and ganciclovir treatment.
OBJECTIVE
Our aim was to study whether herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV)-mediated lentiviral gene transfer diminished graft-versus-host disease (GVHD) in a mouse model of allogeneic bone marrow transplantation (BMT).


METHODS
Donor splenic lymphocytes infected with lentiviral vectors carrying HSV-TK were mixed with donor bone marrow cells before cotransplantation into recipient mice irradiated with 60Co gamma-ray. GCV (25 mg/kg/d) was intraperitoneally administered beginning on days 0, 7, and 12 after transplantation for 7 days. The survival time, severity and incidence of GVHD, T-lymphocyte immune reconstitution, and percentage of allogeneic chimeras were observed after allo-BMT.


RESULTS
The average survival times of mice in the TK/GCV 0 day, TK/GCV 7 day, and TK/GCV 12 day groups were 30.10 +/- 5.21, 36.40 +/- 5.28, and 28.20 +/- 4.82 days, respectively, all of which were longer than that of the control group (P < .05). The effect at 7 days was best: it was significantly different from the 0 and 12 day groups. The incidence of grade III to IV GVHD after allo-BMT in the control group was 100%, whereas there were pathological changes of grade II to III GVHD in the experimental groups. After allo-BMT, CD4+ and CD4+/CD8+ T lymphocytes in the experimental groups were all higher than in the control group (P < .05), but CD8+ T lymphocyte percentages were all lower than the latter.


CONCLUSIONS
HSV-TK/GCV expression mediated by lentiviral transduction plays a role to prevent and treat GVHD after allo-BMT. The effect to control GVHD was most pronounced when GCV was administered on day 7 after transplantation.
Xu
K
K
Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, Jiangsu, People's Republic of China. lihmd@163.com
Zhu
F
F
Du
B
B
Gao
F
F
Cheng
H
H
Pan
X
X
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology*; D005720:Gamma Rays; D015774:Ganciclovir / Q000627:therapeutic use*; D006085:Graft Survival / Q000276:immunology; D006086:Graft vs Host Disease / Q000473:pathology / Q000517:prevention & control*; D016086:Lentivirus / Q000187:drug effects* / Q000502:physiology; D008214:Lymphocytes / Q000276:immunology / Q000821:virology; D051379:Mice; D018139:Simplexvirus / Q000187:drug effects / Q000201:enzymology*; D013154:Spleen / Q000276:immunology / Q000821:virology; D013937:Thymidine Kinase / Q000187:drug effects / Q000378:metabolism*; D014184:Transplantation, Homologous
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir